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Cellular Oncology
Published in: Cellular Oncology 1/2024

Open Access 07-09-2023 | Osteosarcoma | Research

Host-derived growth factors drive ERK phosphorylation and MCL1 expression to promote osteosarcoma cell survival during metastatic lung colonization

Authors: Camille A. McAloney, Rawan Makkawi, Yogesh Budhathoki, Matthew V. Cannon, Emily M. Franz, Amy C. Gross, Maren Cam, Tatyana A. Vetter, Rebekka Duhen, Alexander E. Davies, Ryan D. Roberts

Published in: Cellular Oncology | Issue 1/2024

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Abstract

Purpose

For patients with osteosarcoma, disease-related mortality most often results from lung metastasis—a phenomenon shared with many solid tumors. While established metastatic lesions behave aggressively, very few of the tumor cells that reach the lung will survive. By identifying mechanisms that facilitate survival of disseminated tumor cells, we can develop therapeutic strategies that prevent and treat metastasis.

Methods

We analyzed single cell RNA-sequencing (scRNAseq) data from murine metastasis-bearing lungs to interrogate changes in both host and tumor cells during colonization. We used these data to elucidate pathways that become activated in cells that survive dissemination and identify candidate host-derived signals that drive activation. We validated these findings through live cell reporter systems, immunocytochemistry, and fluorescent immunohistochemistry. We then validated the functional relevance of key candidates using pharmacologic inhibition in models of metastatic osteosarcoma.

Results

Expression patterns suggest that the MAPK pathway is significantly elevated in early and established metastases. MAPK activity correlates with expression of anti-apoptotic genes, especially MCL1. Niche cells produce growth factors that increase ERK phosphorylation and MCL1 expression in tumor cells. Both early and established metastases are vulnerable to MCL1 inhibition, but not MEK inhibition in vivo. Combining MCL1 inhibition with chemotherapy both prevented colonization and eliminated established metastases in murine models of osteosarcoma.

Conclusion

Niche-derived growth factors drive MAPK activity and MCL1 expression in osteosarcoma, promoting metastatic colonization. Although later metastases produce less MCL1, they remain dependent on it. MCL1 is a promising target for clinical trials in both human and canine patients.
Appendix
Available only for authorised users
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Metadata
Title
Host-derived growth factors drive ERK phosphorylation and MCL1 expression to promote osteosarcoma cell survival during metastatic lung colonization
Authors
Camille A. McAloney
Rawan Makkawi
Yogesh Budhathoki
Matthew V. Cannon
Emily M. Franz
Amy C. Gross
Maren Cam
Tatyana A. Vetter
Rebekka Duhen
Alexander E. Davies
Ryan D. Roberts
Publication date
07-09-2023
Publisher
Springer Netherlands
Published in
Cellular Oncology / Issue 1/2024
Print ISSN: 2211-3428
Electronic ISSN: 2211-3436
DOI
https://doi.org/10.1007/s13402-023-00867-w

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